Triple negative (PR-, ER-, HER-2-) breast cancer (TNBC), which disproportionately afflicts premenopausal and minority women, has a very poor prognosis. Current TNBC treatment consists of combination chemotherapy which is toxic to the patient, increases morbidity and decreases quality of life. Considering these limitations, and high relapse rate, TNBC poses a major clinical challenge, and developing new agents that are effective and safe is a critical unmet need. Veana Therapeutics has developed a novel compound, alpha-tocopheryloxyacetic acid (a-TEA), which kills cancer cells and stimulates the immune system. Veana is conducting a first-in-human safety trial of oral a-TEA in patients with advanced cancer. At the lowest doses tested so far, a-TEA is safe, and has stopped tumor from growing in 70% of patients. Cancer treatment has been revolutionized by a new class of antibodies known as immune checkpoint inhibitors, which ?release the brakes? so that immune cells (T cells) can more effectively destroy cancer cells. The safest of this class, anti-Programmed Death-1 (anti-PD-1) demonstrated objective clinical responses in patients, which led to FDA approval for the treatment of melanoma, kidney, bladder and head and neck cancers. Unfortunately, anti-PD-1 has not demonstrated the same activity in advanced TNBC patients. The finding that only a few patients obtain long-term benefit with anti-PD-1 therapy has fueled combinations with other agents with the goal of increasing curative responses in more patients. However, a major obstacle to achieving this goal is determining the best dosing and sequence of these combination therapies. Due to its unique property to ?prime? the immune system, a-TEA is an ideal candidate to combine with anti-PD-1 in TNBC. The goal of this application is to conduct pre-clinical studies to determine the optimum dose of a-TEA and schedule of anti-PD-1 that will deliver the best therapeutic outcome. We will pursue three specific aims to achieve this goal: Aim 1 will assess the impact of varying doses of a-TEA and timing of anti-PD-1 on tumor growth, metastasis, and survival; Aim 2 will identify surrogate immunologic biomarkers of effective combination therapy by assessing expression of T cell activation and ?exhaustion? markers, cell proliferation, cytokine production, frequency of tumor-infiltrating T cells and expression of the PD-1 ligand, PD- L1 by immunohistochemical staining of tumor tissue. Aim 3 will compare the antitumor activity and toxicity profile of a-TEA, doxorubicin, and paclitaxel in combination with anti-PD-1 by assessing tumor growth and survival, and performing hematological analysis (complete blood counts, blood chemistry analysis), necropsy and examination of tissues and organs. Successful completion of the studies and realization of the milestones will lay the groundwork for a Phase II grant application to evaluate safety of a-TEA plus anti-PD-1 in a first-in-human combination trial in patients with TNBC. Demonstration of efficacy in subsequent Phase II/III trials could lead to FDA-approval which would pave the way for commercialization of a-TEA as a companion drug with anti-PD-1 for treating TNBC.